Purpose: Abiraterone acetate (AA), an inhibitor of CYP17A1, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells.
Experimental Design:We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA-seq and phospho-kinase array screenings were performed to discover that the cAMP response element-CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development.
Results:The drug-resistant cell lines are phenotypically stable without drug selections, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation re-sensitized AA-resistant cells to AA. AA treatment increases intracellular cAMP levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells, since AAresistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further
177 Background: The androgen receptor (AR) remains an essential target in castration resistant prostate cancer (CRPC). Abiraterone acetate (AA), an inhibitor of CYP17A1, is an FDA approved drug for metastatic CRPC. AA can also be converted to the more active metabolite 4-abiraterone in vivo, which blocks multiple steroidogenic enzymes and antagonizes AR. However, not all patients respond to AA and AA resistance ultimately develops in those patients who initially respond. Methods: We established several AA resistant prostate cancer cell lines and performed a comprehensive study of mechanisms involved in the development of AA resistance. The AA-resistant cell lines are phenotypically stable with aggressive invasive features. By RNA-seq and phospho-kinase array screening, we found that the cAMP response element-CRE binding protein 1 (CREB1) is activated in AA resistant cell lines. Results: Over-expression of the wild type CREB1 or treatment with Forskolin desensitizes the cellular response to AA, while over-expressing the mutated CREB1 (S133A, an essential kinase site) did not significantly affect cell sensitivity to AA. Blocking pCREB1 with the CREB inhibitor increased the sensitivity of AA resistant cell lines to AA. The activation of pCREB1 in AA resistant cell lines may potentially activate the CBP/p300 complex. Our data demonstrated that treatment with a low dose of AA strongly synergistic the efficacy of CBP/p300 inhibitors in prostate cancer cell lines. Taken together, we found that AA treatment activates CREB1 and pCREB1 may interact with the CBP/p300 complex, leading to global gene expression alterations, which subsequently result in the development of drug resistance. Conclusions: Our study indicates that AR-targeted treatment potentially fosters de novo genetic and epigenetic alterations associated with progression. A more effective AR-targeted treatment for CRPC may be developed by considering low doses of multiple targets involved in the development of resistance pathways.
<p>Table S3. Differential express genes enrichment analysis in LNCaP-abl-AAr and LNCaP-abl. ES= enrichment score, NES= normalized enrichment score, NOM = nominal, FDR = false discovery rate. The significant related genes were defined with an NOM p-val less than 0.01 and FDR q-val less than 0.25.</p>
<p>Table S2. Differential express genes enrichment analysis in LAPC4-AAr and LAPC4.ES= enrichment score, NES= normalized enrichment score, NOM = nominal, FDR = false discovery rate. The significant related genes were defined with an NOM p-val less than 0.01 and FDR q-val less than 0.25.</p>
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